Loss of tuberin, the tuberous-sclerosis-complex-2 gene product is associated with angiogenesis

Background: Tuberous sclerosis complex (TSC) is an autosomal dominantly inh erited disorder associated with an alteration of the TSC2 tumor suppressor gene which encodes for the protein product tuberin. The disease is characte rized by the development of hamartomas, e.g. cutaneous angiofibromas which consist of vascular cells, interstitial cells, and normal components of the skin. The Eker rat model, an animal model of inherited cancer, has been sh own to carry a mutation of TSC2. Methods: Immunohistochemical analyses of human angiofibromas were performed using antibodies directed against tuberin and angiogenic growth factors. P roliferation of human dermal microvascular endothelial cells (HDMEC) was de termined after incubation with the supernatants of TSC2 (+/+) and TSC2 (-/- ) rat embryonic fibroblasts (REF) that were derived from the Eker strain. Results: Loss of the expression of tuberin was observed in the interstitial cells of 13 of 39 angiofibromas. The expression of tuberin was retained in the vascular cells. In all analyzed angiofibromas, the angiogenic factors bFGF, PD-ECGF, VEGF and angiogenin were detected in the interstitial cells and/or vascular cells. Expression of PDGF-B and TGF-beta1 was weak. Tissue culture supernatants from TSC2 (-/-) REF stimulated the growth of HDMEC sig nificantly more than supernatants from TSC2 (+/+) REF. Conclusion: A functional loss of tuberin may stimulate vascular growth.